Integrating genetics and metabolomics from multi-ethnic and multi-fluid data reveals putative mechanisms for age-related macular degeneration

Age-related macular degeneration (AMD) is a leading cause of blindness in older adults. Investigating shared genetic components between metabolites and AMD can enhance our understanding of its pathogenesis. We conduct metabolite genome-wide association studies (mGWASs) using multi-ethnic genetic and metabolomic data from up to 28,000 participants. With bidirectional Mendelian randomization analysis involving 16,144 advanced AMD cases and 17,832 controls, we identify 108 putatively causal relationships between plasma metabolites and advanced AMD. These metabolites are enriched in glycerophospholipid metabolism, lysophospholipid, triradylcglycerol, and long chain polyunsaturated fatty acid pathways. Bayesian genetic colocalization analysis and a customized metabolome-wide association approach prioritize putative causal AMD-associated metabolites. We find limited evidence linking urine metabolites to AMD risk. Our study emphasizes the contribution of plasma metabolites, particularly lipid-related pathways and genes, to AMD risk and uncovers numerous putative causal associations between metabolites and AMD risk. [Display omitted] •Large-scale metabolite genome-wide association studies identify mQTLs in plasma and urine•Two-sample Mendelian randomization analysis uncovers 108 plasma metabolites associated with AMD•AMD-associated metabolites are enriched in lipid-related pathways•Systematic exploration of metabolite connections with AMD subtypes and lipid biomarkers In this study, Han et al. conduct large-scale integrative genetic and metabolomic analysis and discover 108 plasma metabolites associated with advanced age-related macular degeneration. The identified metabolites are enriched in pathways of glycerophospholipid metabolism, lysophospholipid, triradylcglycerols, and long-chain polyunsaturated fatty acids, providing insight into their potential in AMD pathogenesis.